Discussion
This study is the first to specifically evaluate and assess the incidence, predictors, and impact of MLBCs on long-term prognosis after TAVR. The main results of the present study are as follows: 1) among patients treated with TAVR, MLBCs (≥30 days) were relatively frequent, occurring in approximately 6% of patients; 2) GI and neurological origin were the most frequent identifiable sites of bleeding; 3) independent predictors of MLBCs after TAVR included the presence of AF, residual moderate or severe PVL, baseline hemoglobin, and increased left ventricular mass; and 4) MLBCs were associated with an increased rate of mortality and morbidity between 30 days and 1 year.
To the best of our knowledge, the present study is the first to specifically examine bleeding events after TAVR beyond the periprocedural period (≥30 days) and to demonstrate their strong association with increased mortality. Indeed, MLBCs were associated with a 4-fold increase in late mortality among the TAVR population enrolled in the PARTNER trial. Several groups have previously described the negative impact of periprocedural bleeding and red blood cell transfusions after TAVR procedures. The present study reinforces and extends beyond the periprocedural period the detrimental effect of major bleeding events and identifies a potential area for improved patient care. Although much attention initially focused on the improvement of acute outcomes (advances in device technologies, optimization of implantation techniques, and enhanced operator experience), leading to a dramatic reduction in periprocedural complications, this study demonstrates that reducing later adverse events (such as MLBCs) is also crucial if long-term prognosis is to be improved. Fortunately, prospective studies are ongoing (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation [NCT01559298]) and are expected to provide some answers to this important question.
Previous reports demonstrated that periprocedural bleeding was driven mainly by anatomical and technical considerations. However, MLBCs appear to be related mainly to patients' bleeding susceptibility, which is often "triggered" by the antithrombotic agent used. Unsurprisingly, GI bleeding was the most frequently identifiable source of major bleeding after 30 days. Bleeding from arteriovenous malformation distributed throughout the GI tract is a well-described syndrome (Heyde's syndrome) associated with severe aortic stenosis, accounting for a significant proportion of GI bleeding in this population. Similarly, benign and malignant tumors are frequent in this group of patients. Appropriate screening, such as gastroscopy, colonoscopy (either before or soon after the TAVR procedure), and the use of gastroprotection (i.e., proton pump inhibition), could be considered during the high-risk period and may help prevent a proportion of these GI bleeds. Further studies are needed to evaluate the risk and benefits of these strategies.
The association between MLBCs and moderate or severe PVL is previously unrecognized and may represent a mechanism underlying the excess mortality and morbidity associated with residual moderate or severe PVL among patients surviving beyond 30 days post-TAVR. Indeed, several groups have previously noted that high shear stress and flow turbulence may lead to the loss (cleavage) of essential proaggregation proteins (high–molecular weight von Willebrand factor), leading to an increased susceptibility to bleeding (acquired von Willebrand disease type 2A). This hematologic disturbance has been shown to rapidly resolve with treatment of the aortic stenosis or any anatomic situation causing high-flow turbulence. Our findings, in which patients with underlying high-risk bleeding profiles, combined with highly turbulent flow through "crushed" heavily calcified native valve leaflets and underexpanded leaking prostheses, suggest that post-TAVR paravalvular aortic regurgitation may represent the perfect storm for acquired thrombophilia, ultimately leading to major bleeding events. This biological phenomenon may be amplified by using aggressive antiplatelet therapy and/or anticoagulation therapy. This finding reinforces the importance of optimizing valve implantation to minimize the presence of significant residual PVL, not only to avoid its detrimental hemodynamic effect on the left ventricle but also to restore a normal "biological-hematological" homeostasis and decrease the risk for subsequent major bleeding events. The association of increased left ventricular mass with future MLBCs is intriguing and interesting. Although this association is most likely multifactorial, the hypothesis of increased flow turbulence leading to increased bleeding tendency may also be an explanation. That said, given the retrospective nature of our analysis and the presence of potential residual confounders despite a well-conducted multivariate analysis, this finding can only be identified as hypothesis generating at this point.
Patients with AF, at either baseline or post-procedurally, have been shown to represent a high-risk population with worse outcomes and increased mortality after TAVR. Our report reinforces these previous results, showing that patients with AF have a higher rate of death, because of a higher occurrence of MLBCs or thromboembolic events. Further studies may help determine the best strategies to manage AF among this group of high-risk patients.
Study Strengths and Limitations
This study has some important strengths. It is the largest study to use both an independent echocardiographic core laboratory and an independent clinical events committee, providing extensive analysis and allowing the identification of a meaningful association between specific echocardiographic parameters (e.g., PVL) and important clinical findings (e.g., bleeding). Nonetheless, several important limitations of the present analysis should be acknowledged. First and foremost, systematic capture of anticoagulation regimens (e.g., with warfarin) was not performed during the different PARTNER studies. Although we acknowledge the central importance of such information when appraising causes and correlates of major bleeding events, our report still brings meaningful insight regarding the incidence and impact of MLBCs after TAVR and raises awareness of the importance and urgency to better define the safest and most effective post-procedural antithrombotic therapy, particularly among patients with AF. That said, given the high thromboembolic risk profile of this population, most of the TAVR patients diagnosed with AF were on, or should have received, anticoagulation therapy. It is likely that the strong association between AF and bleeding, as well as AF and mortality, in the TAVR population represents the effect of oral anticoagulation either alone or in combination with antiplatelet therapy in such patients. This finding clearly illustrates the extreme challenge of treated AF in the TAVR population and the need to better define the optimal antithrombotic regimens in such patients.
Second, patients with recent GI bleeding or neurological events (ischemic or hemorrhagic) were excluded from the PARTNER trial. The inclusion of such patients (as in real-world practice) would have likely resulted in an even higher rate of MLBCs.
Third, the definition of major bleeding used in the present report lies at the extreme range of bleeding severity, particularly in the outpatient setting. It is possible that a more refined, detailed bleeding classification, such as that proposed by the Bleeding Academic Research Consortium (BARC), could have been used and may have led to different findings. The bleeding definitions used in the present report correspond approximately to BARC classes 3 and 5, depending on the severity (leading to death or not). However, BARC classification has not been validated in the TAVR space, and data collection unfortunately does not allow BARC bleeding readjudication. Finally, although we adjusted for imbalances in a number of important covariates, potential unmeasured confounders may still be present. The results of this observational post hoc analysis should therefore be considered hypothesis generating.